The advantages of applying enzymatic resolution to the preparation of optically active molecules have become well recognized. However, as the structure-activity correlations of most enzymatic reactions remain to be explored, predictions of the catalytic efficiency and stereochemical preference for a particular compound prove to be difficult; Sih, C. J.; Gu, Q. M.; Reddy, D. R. in Trends in Medicinal Chemistry, Mutschler E., Winterfieldt, E. Eds.; VCH, New York, 1987; pp. 181 and Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656. Although, with the recent advent of protein crystallography and computer graphics, researchers are now able to scrutinize the conformation of biocatalytic domains; Brady, L.; Brzozowski, A. M.; Derewenda, Z. S.; Dodson, E.; Dodson, G.; Tolley, S.; Turkenburg, J. P.; Christiansen, L.; Huge-Jensen, B.; Norskov, L.; Thim, L.; Menge, U. Nature 1990, 343, 767; Winkler, F. K.; D'Arcy, A.; Hunziker, W. ibid, 771. The establishment of a complete database appears to be far from realization. Consequently, by and large, design of an enzyme substrate to optimize chemical/optical yields has been conducted on a trial-and-error basis.
For rational substrate design, computer-aided molecular modeling is used. This approach provides insight into the energy-minimized conformations of substrate molecules, and thus provides a viable means to identify steric factors crucial to catalytic turnover and/or enantiomeric differentiation.
The preferred embodiment of the invention will be described in reference to an efficient enzymatic access to optically active propranolol (1). Compound 1 was chosen as the model in light of two considerations: (a) as (S)-1 is the active antipode in block .beta.-adrenergic receptors, the development of an efficient preparation merits attention; Backvail, J. E.; Bjorkman, E. E.; Bystrom, S. E. Tetrahedron Lett. 1982, 23, 943; Katsuki, T. Tetrahedron Lett. 1984, 25, 2821; Miyano S.; Lu, L. D. L.; Viti, S. M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 4350; and Klunder, J. M.; Soo, Y. K.; Sharpless, K. B. ibid, 1986, 51, 3710 (examples of chemical asymetric synthesis) and Iriuchijima, S.; Keiyu, A.; Kojima, N. Agri, Biol. Chem. 1982, 46, 1593; Marsuo, N.; Ohno, N.; Tetrahedron Lett. 1985, 26, 5533; Fuganti, C.; Grasselli, P.; Seneci, P. F.; Servi, S. Tetraherdon Lett. 1986, 27, 2061; Terao, Y.; Murata, M.; Achiwa, K. Tetrahedron Lett. 1988, 29, 5173; and Wang, Y. F.; Chen, S. T.; Liu, K. K. C.; Wong, C. H. Tetrahedron Lett. 1989, 30, 1917 (enzymatically prepared precursors); and (b) previous attempts by a number of groups to effect direct enzymatic resolution of 1 have not been successful so far; Jpn. Kokai Tokyo Koho JP 62 151,196 (Chem Abstr. 1988, 108, 110832d); and Jpn. Kokai Tokyo Koho JP 63 94,992 (Chem Abstr. 1989, 110, 93558r).